2-Alkoxy(and 2-alkoxyalkyl)-2-pyridyl-thioacetamides

ABSTRACT

The compounds are 2-alkoxy(and 2-alkoxyalkyl)-2-heterocyclicthioacetamides which are inhibitors of gastric acid secretion.

United States Patent Van Hoeven et al.

[ Sept. 23, 1975 2-ALKOXY(AND Z-ALKOXYALKYL)-2-PYRIDYL- THIOACETAMIDESInventors: Helene E. Bowman Van Hoeven,

Wallingford; L. Martin Brenner, Upper Darby; Bernard Loev, Broomall, allof Pa.

SmithKline Corporation, Philadelphia, Pa.

Filed: Aug. 9, 1973 Appl. No.: 386,898

Related U.S. Application Data Continuation-impart of Ser. No. 284,375,Aug. 28, 1972, abandoned, which is a continuation-in-part of Ser. No.248,512, April 28, 1972, abandoned.

Assignee:

[51] Int. Cl. C071) 213/83 [58] Field of Search 260/2948 E, 293.69

References Cited UNITED STATES PATENTS 7/1974 Loev 260/2948 E PrimaryExaminerAlan L. Rotrnan Attorney, Agent, or Firm-Joan S. Keps; RichardD. Foggio; William H. Edgerton [57] ABSTRACT The compounds are2-a1koxy(and 2-a1koxya1kyl)-2- heterocyclic-thioacetamides which areinhibitors of gastric acid secretion.

10 Claims, No Drawings 1 2ALKOXY(AND Z-ALKOXYALKYL)-2-PYRIDYL-THTOACETAMIDES CROSS REFERENCE TO RELATED APPLICATIONS This applicationis a continuation-in-part of Ser. No. 284,375, filed Aug. 28, 1972, nowabandoned, which is a continuation-in-part of Ser. No. 248,512, filedApr. 28, 1972 now abandoned.

This invention relates to new 2-alkoxy(and2-alkoxyalkyl)-2-heterocyclic-thioacetamides having pharma cologicalactivity. In particular, these compounds in hibit gastric acidsecretion.

The compounds of this invention are represented by the followingformula:

FORMULA l R, s all... l z). -11,

in which:

m is O, l or 2;

R, is 2-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyrazinyl, 2-pyrrolyl,2-quinolyl, 2-thiazolyl or 4-thiazolyl;

R is lower alkyl, allyl or cyclopropanemethyl;

alkoxy or halogen may be incorporated on the heterocyclic rings. Thesesubstituted compounds are used as are the parent compounds.

Preferred compounds of this invention are represented by Formula I inwhich m is 0, R is methyl, R is NH-(lower alkyl), N(lower alkyl): orNl-l-(CH cycloalkyl and RQis hydrogen or methyl.

Most preferably, in the compounds of Formula 1, R is 2-pyridyl. Also,preferably, m is O.

Particularly advantageous compounds of this invention are2-methoxy-N-methyl-2-(2- pyridyl)thioacetamide andZ-methoxy-N,N-dimethyl-Z- (2-pyridyl)thiopropanamide.

The compounds of this invention produce inhibition of gastric acidsecretion. This activity is demonstrated by administration to pylorusligated rats at doses of about 1.0 mgjkg. to about mg./kg. orally orintramuscularly. Also, this activity is demonstrated by administrationto chronic gastric fistula rats (Brodie et al., Amer. J. Physiol.202:812-814, 1962) at doses of about l0 mg./kg. to about 50 mgJkg.orally. In these procedures, compounds which produce an increase ingastric pH or a decrease in the volume of gastric juice or both areconsidered active.

These compounds show antiulcer activity, for example in therestraint-stress method, in which on oral administration to rats thesecompounds inhibit the development of experimental ulcers.

The compounds of this invention are prepared by the followingprocedures:

R. R base R S g H R. H+ R -CH R'NCS R,-c-C-R,' I L). l zh Kills) X o-R204:,

R, 0 R, o R, o i g u A n R,- H- -0-R"+R, -COR"- R,- c-NH,

(II-l2) f 2)I| -R, O-R,

R, s R, s R,- -d-R,"e R, c-lt NH, ---R,- CN

( H2). z)- z) o-R R, -R,

The terms m, R,, R and RI, are as defined above, X is chloro or bromo, Ris lower alkyl, phenyl or (CI-1 cycloalkyl, R is NH-(lower alkyl),NH-phenyl or NH- (CH ),,-cycloalkyl, R" is lower alkyl, preferablymethyl or ethyl and R is NH-(lower alkyl), N(lower alkyl) NH-phenyl orNl-l-(CH ),,-cycloalkyl.

According to procedure I, a haloalkyl-heterocycle is reacted with analkoxide, such as sodium alkoxide, and the resultingalkoxyalkyl-heterocycle is reacted with a strong base such as phenyl orbutyl lithium and then with an appropriate isothiocyanate to give N-substituted 2-alkoxy(and 2-alkoxyalkyl)-2-heterocyclic-thioacetamides ofthis invention. The process of reacting an alkoxyalkyl-heterocycle witha strong base and then with an isothiocyanate to give N-substituted2-alkoxy(and 2-alkoxyalkyl)-2-heterocyclicthioacetamides of thisinvention is invention. L

Alternatively, the alkoxyalkyl-heterocycles may be prepared by reactinga heterocyclic-alkanol with an appropriate halide, for example a loweralkyl, allyl 'or cyclopropanemethyl chloride or bromide, in the presenceof a base such as sodium hydride.

also an object of this Accordingto procedure II, a lower alkyl2-heterocyclic-acetate is converted to the 2-alkoxy compound by reactingwith N-bromo or N-chlorosuccinimide and reacting the resulting 2-bromoor 2-chloro compound with a sodium alkoxide; the resulting lower alkyl2- alkoxy(or 2-alkoxyalkyl)-2-heterocyclic-acetate is con- The loweralkyl 2-alkoxy(or 2-alkoxyalkyl)-2-heterocyclic-acetate intermediates inprocedure li may also beprepared by reacting an alkoxyalkyl-heterocycle(which is an intermediate in procedure I) with a strong base such asphenyl lithium and a lower alkyl chloroformate.

Alternatively, the N-substituted thioacetamides of this invention may beprepared by the following procedures:

a. reacting a lower alkyl 2-alkoxy(or 2-alkoxyalkyl)-2-heterocyclic-acetate with the appropriate substituted amine andtreating the resulting N-substituted 2- alkoxy(or2-alkoxy-alkyl)-2-heterocyclic-acetamide with phosphorus pentasulfide;

b. reacting an alkoxyalkyl-heterocycle with a strong base such as phenyllithium and a N,N-di-lower alkylcarbamoyl chloride and treating theresulting N,N-diloweralkyl-2-alkoxy-(or2-alkoxyalkyl)-2-heterocyclicacetamide with phosphoruspentasulfide;

c. reacting an alkoxyalkyl-heterocycle with a strong base such as phenyllithium and a N,N-di-lower alkylthiocarbamoyl chloride.

The pharmaceutically acceptable, acid addition salts of the compounds ofFormula I are formed with organic and inorganic acids by methods knownto the art. For example, the base is reacted with an organic orinorganic acid in aqueous miscible solvent, such as acetone or ethanol,with isolation of the salt by concentration and cooling or in aqueousimmiscible solvent, such as ethyl ether or chloroform, with the desiredsalt separating directly. Exemplary of the salts which are included inthis invention are maleate, fumarate, succinate, oxalate, benzoate,methanesulfonate, ethanedisulfonate, benzenesulfonate, acetate,propionate, tartrate, citrate, camphorsulfonate, hydrochloride,hydrobromide, sulfate, sulfamate, phosphate and nitrate salts.

The compounds of this invention are administered internally eitherparenterally, rectally or, preferably, orally in an amount to producethe desired biological activity.

Preferably, the compounds are administered in conventional dosage formsprepared by combining an appropriate close of the compound with standardpharmaceutical carriers. Y

The pharmaceutical carrier may be for example a solid or a liquid.Exemplary of solid carriers are lactose,

magnesium stearate, terra alba, sucrose, talc, stearic acid, gelatin,agar, pectin, acacia or cocoa butter. The amount of solid carrier willvary widely but preferably will be from about 25 mg. to about 1 gm.Exemplary of liquid carriers are syrup, peanut-oil, olive oil, sesameoil, propylene glycol, polyethylene glycol (mol. wt. 200-400) and water.The carrier or diluent may include a time delay material well known tothe art such as, for example, glyceryl monostearate or glyceryldistearate alone or with a wax.

A widevariety of pharmaceutical forms can be employed, for example thepreparation may take the form of, tablets, capsules, powders,suppositories, troches, lozenges, syrups, emulsions, sterile injectableliquids or liquid suspensions or solutions.

The pharmaceutical compositions are prepared by conventional techniquesinvolving procedures such as mixing, granulating and compressing ordissolving the ingredients as appropriate to the desired preparation.

The pharmaceutical compositions of this invention contain a compound ofFormula I or a pharmaceutically acceptable acid addition salt thereof inan amount of from about 10 mg. to about 500 mg.

The methods of inhibiting gastric acid secretion in accordance with thisinvention comprise administering internally to an animal an effectiveamount of a compound of Formula l or a pharmaceutically acceptable acidaddition salt thereof. The active ingredient will preferably beadministered in dosage unit form as described hereabove. Preferably, theactive ingredient will be administered in a total dosage of from about10 mg. to about 2500 mg. Advantageously, equal doses will beadministered one to four times per day.

When the administration is carried out as described above, gastric acidsecretion is inhibited.

One skilled in the art will recognize that in determining the amounts ofthe active ingredient in the claimed compositions and used in theclaimed methods the activity of the chemical ingredient as well as thesize of the host animal must be considered.

It will be apparent to one skilled in the art that the compounds of thisinvention have an asymmetric carbon atom and thus may be present asoptical isomers. The connotation of the formulas presented herein is toinclude all isomers, the separated isomers as well as mixtures thereof.Preferably, the optically active thioacetamides are prepared (a) by theuse of optically active strong acids, such as camphorsulfonic acid orphenethylsulfamic acid, to separate the optical isomers of thethioacetamides or (b) by the use of optically active bases, such asa-methylbenzylamine or strychnine, to separate the optical isomers of2-alkoxy(or 2-alkoxyalkyl)-2-heterocyclic acetic acids (prepared byhydrolysis of the esters prepared by the method described in procedure(II) which are then esterified and converted to the thioacetamidesaccording to procedure.

The'terms lower alkyl and lower alkoxy where used herein denote groupshaving 1-4 carbon atoms and halogen denotes chloro, bromo or fluoro.

The following examples are not limiting but are illustrative of thecompounds of this invention and processes for their preparation.

1 EXAMPLE 1 2-(Chloromethy1)pyridine hydrochloride (16.3 g., 0.1 mole)is dissolved in 100 ml. of methanol. Freshly prepared sodium methoxide(5g., 0.22 mole of sodium dissolved in 150 ml. of methanol) is addeddropwise. The resulting mixture is heated at reflux for 18 hours, thenfiltered. The filtrate is concentrated. Water and ether are added, theaqueous phase is extracted with ether and the combined ethereal phasesare washed with water and saturated aqueous sodium chloride, then driedover magnesium sulfate, concentrated and distilled to give2-(methoxymethyl)pyridine.

Alternatively, 0.1 mole of 2-(chloromethyl)pyridine and 0.11 mole ofsodium methoxide are used in the above procedure to give2-(methyoxymethyl)pyridine.

Also, 2-(methoxymethyl)pyridine is prepared by the following alternativeprocedure. A mixture of 10.9 gfof 2-pyridinemethanol and 2.4 g. ofsodium hydride in 50 ml. of dimethylsulfoxide is warmed on a steam bathfor minutes, then cooled to room temperature. Methyl iodide (14.2 g.) isadded and then the mixture is heated at 40C. for one hour. Water (150ml.) is then added and the mixture is extracted with ether. The extractsare dried, concentrated and distilled to give 2-(methoxymethyl)pyridine.

2-(Methoxymethyl)pyridine (4.4 g., 0.036 mole), dissolved in ml. of drybenzene, is added dropwise to 20 ml. of 2M phenyl lithium (0.04 mole) inbenzene/ether with cooling. The mixture is stirred for minutes, thenmethyl isothiocyanate (2.6 g., 0.03 mole), dissolved in ml. of drybenzene, is added dropwise with cooling. The resulting solution isstirred overnight. An equal volume of water is added and the solution iscooled and made acidic with 10% hydrochloric acid. The phases areseparated, the organic phase is washed with water and the combinedaqueous phases are made basic to about pH 9, then extracted withchloroform. The chloroform extracts are washed with water and dried overmagnesium sulfate. Filtration and removal of solvent gives a residuewhich is recrystallized from isopropyl ether/ethanol to give 2-methoxy-N-methyl-2-(2-pyridyl)thioacetamide, m.p. 104-l05C.

EXAMPLE 2 By the procedure of Example 1, using in place of sodiummethoxide, the following sodium alkoxides:

sodium ethoxide sodium propoxide sodium butoxide sodium allyloxidesodium cyclopropanemethoxide the products are, respectively:

2-ethoxy-N-methyl-2-( 2-pyridyl )thioacetamideN-methyl-2-propoxy-2-(2-pyridyl)thioacetamide 2-butoxy-N-methyl-2-(2-pyridyl )thioacetamide 2-allyloxy-N-methyl-2-(2-pyridyl)thioacetamide2-cyclopropanemethoxy-N-methyl-2-(2- pyridyl)thioac etamide.

EXAMPLE 3 By the procedure of Example 1, using in place of 2-(chloromethyl)pyridine, the following:

2-(chloromethyl)pyrazine 2-(chloromethyl)quinoline2-(chloromethyl)thiazole EXAMPLE 4 A mixture of 6.3 g. of2-pyrrolemethanol and 25 ml. of thionyl chloride is heated on a steambath for 4 hours. The mixture is then concentrated under reducedpressure and the residue is dissolved in waterpbasified with 5% aqueoussodium bicarbonate solutionand'extracted with ether. The extracts aredried, concentrated and distilled to give 2-(chloromethyl)'pyrrole.

Using 2-(chloromethyl)pyrrole in place of 2- (chloromethyl)pyridine inthe procedure of Example 1 gives 2-methoxy-N-methyl-2-(2-pyrrolyl)thioacetamide.

In the same manner, converting 2- pyrimidinemethanol to2-(chloromethyl)pyrimidine and using 2-(chloromethyl)-pyrimidine in theprocedure of Example 1, the product is 2-m ethoxy-N-methyl-2-(2-pyrimidy1)thioacetamide.

EXAMPLE 5 4-Pyrimidinecarboxylic acid is reduced using lithium aluminumhydride in ether to give pyrimidinemethanol.

4-Pyrimidinemethanol is converted to 4- (chloromethyl)-pyrimidine by theprocedure of Example 4.

Using 4-(chloromethyl)pyrimidine in the procedure of Example 1, theproduct is 2methoxy-N-methyl-2- (4-pyrimidyl)-thioacetamide.

EXAMPLE 6 Toa solution containing 12.1 g. (0.08 mole) of methyl 2-(2-pyridyl)acetate in 120 ml. of carbon tetrachloride is added 14.8 g.(0.084 mole) of N- bromosuccinimide and 0.3 g. of dibenzoylperoxide. Thesolution is irradiated by means of a sun-lamp source until essentiallyall the solid (succinimide) has risen to the top (about 10-15 minutes).

The solution is filtered aiidthe solvent removed under reduced pressureand without heat to give methyl 2-bromo-2-(2-pyridyl)acetate.

The above prepared 2-bromo compound is dissolved l in ml. of drymethanol and freshly prepared sodium methoxide (0.09 mole) in 100 ml. ofdry methanol is added dropwise. Then the mixture is stirred for threehours at room temperature. The solvent is removed under reduced pressureand without heat to give methyl 2-methoxy-2-(2-pyridyl)acetate.

The above prepared 2-methoxy compound is dissolved in 65 ml. ofconcentrated ammonium hydroxide and the solution is stirred for 6.5hours. The mixture is then concentrated, dissolved in chloroform andextracted twice with brine. The organic phase is dried over magnesiumsulfate and filtered and solvent is removed under reduced pressure togive 2-methoxy-2-(2 pyridyl)acetamide.

To 20 ml. of dry 1,2-dichloroethane containing 2.0 of sodium chloride isadded 3.32 g. of 2-methoxy-2-(2- pyridyl)-acetamide. After stirring atroom temperature for 15 minutes, 1.7 ml. of phosphorus oxychloride isadded. The solution is refluxed for 18 hours.'The solution is thencooled and made basic with aqueous sodium hydroxide solution. Theaqueous phase is extracted three times with chloroform and the combinedchloroform extracts are washed three times with water and once withbrine and dried over magnesium sulfate. Filtration, removal of solventand distillation in vacuo gives 2-methoxy-2-(2-pyridyl)acetonitrile,b.p. 7276C./0.2 mm.

In 125 ml. of dry pyridine containing 4 ml. of triethylamine isdissolved 2.65 g. (0.018 mole) of 2-methoxy- 2-(2-pyridyl)acetonitrile.Hydrogen sulfide is bubbled through the solution for 5.5 hours. Thesolvent is evaporated under reduced pressure and chloroform is added tothe residue. The mixture is allowed to stand at C. for 18 hours. Theprecipitate is filtered off and recrystallized from isopropanol to give2-methoxy- 2-(2-pyridyl)thioacetamide, m.p. l57l 59C.

EXAMPLE 7 By the procedure of Example 6, using in place of methyl2-(2-pyridyl)acetate, the following:

methyl 2-(2-pyrrolyl)acetate ethyl 2-(2-quinolyl)acetate ethyl2-(4-thiazolyl)acetate ethyl 2-(4-methyl-2-thiazolyl)acetate ethyl2-(3-methyl-2-pyrazinyl)acetate the products are, respectively:

2-methoxy-2-(2-pyrrolyl)thioacetamide2-methoxy-2-(2-quinolyl)thioacetamide2-methoxy-2-(4-thiazolyl)thioacetamide2-methoxy-2-(4-methyl-2-thiazolyl)thioacetamide2-methoxy-2-(3-methyl-2-pyrazinyl)thioacetamide.

EXAMPLE 8 2-(4-Pyrimidyl)acetic acid is converted to the correspondingmethyl ester by mixing with methanol, cooling and bubbling in hydrogenchloride, then basifying the mixture, extracting with chloroform andremoving the solvent from the extracts. Using the resulting methyl2-(4-pyrimidyl)acetate in the procedure of Example 6 gives2-methoxy-2-(4- pyrimidyl)thioacetamide.

EXAMPLE 9 A mixture of 7.2 g. of 2-pyrimidinemethanol and ml. of thionylchloride is heated for four hours on a steam bath, then concentratedunder reduced pressure. The residue is dissolved in water and basifiedwith 5% aqueous sodium bicarbonate solution. Extracting with ether, thendrying and concentrating the extracts gives 2-(chloromethyl)pyrimidine.

A solution of 6.8 g. of 2-( chloromethyl)pyrimidine is added dropwise toa solution of 5.2 g. of sodium cyanide in 100 ml. of dimethylsulfoxide.The mixture is heated at 50C. for two hours, then diluted with 150 ml.of 5% aqueous sodium carbonate solution and extracted with ether. Theextract is dried and concen trated to give 2-(2-pyrimidyl)acetonitrile.

A mixture of 2-(2-pyrimidyl)acetonitrile, concentrated sulfuric acid(two molar equivalents) and methanol is heated at reflux for six hours,then concentrated and basified with aqueous sodium carbonate solution.Extracting with chloroform, then concentrating and distilling theextracts under reduced pressure gives methyl 2-(2-pyrimidyl)acetate.

Using methyl 2-(2-pyrimidyl)acetate in the procedure of Example 6, theproduct 'is 2-methoxy-2-(2- pyrimidyl)thioacetamide. v.

In the same manner, from 2-(chloromethyl)pyrazine, the product is2-methoxy-2-(2- pyrazinyl)thioacetamide.

Similarly, from 2-(chloromethyl)thiazole, the product is2-methoxy-2-(2-thiazolyl)thioacetamide.

EXAMPLE 10 A solution of 9.1 g. of 2-methoxy-2-(2-pyridyl)-thioacetamide in a 40% aqueous solution of cyclopropylamine is heated atreflux for'45 minutes. The mixture is cooled and 30 ml. of water isadded. The mixture is extracted with chloroform and the extracts aredried over magnesium sulfate and concentrated to give afterrecrystallizing the residue, N-cyclopropyl-2- methoxy-2-( 2-pyridyl)thioacetamide.

By the same procedure, using the following cycloalkylamines:

cyclobutylamine cyclopentylamine cyclohexylamine the products are,respectively: N-cyclobutyl-2-methoxy-2-( 2-pyridyl )thioacetamideN-cyclopentyl-2-methoxy-2-( 2- pyridyl)thioacetamideNcyclohexyl-Z-methoxy-2-(2- pyridyl)thioacetamide.

EXAMPLE 1 1 Using cyclopropanemethyl isothiocyanate in place of methylisothiocyanate in the procedure of Example 1 givesN-cyclopropanemethyl-2-methoxy-2-( 2- pyridyl)thioacetamide.

EXAMPLE 12 Alternatively, N-cyclopropanemethyl-2-methoxy-2-(2-pyridyl)thioacetamide is prepared by the following procedure.

A solution of 6.0 g. of cyclopropanemethylamine hydrochloride and 4.7 g.of sodium bicarbonate in ml. of water is added to 5.4 g. of2-methoxy-2-(2- pyridyl)thioacetamide. The reaction mixture is heated ona steam bath with stirring for four hours. The mixture is then cooledand 25 ml. of water is added. The reaction mixture is extracted threetimes with chloroform. The chloroform extracts are combined, dried overmagnesium sulfate and then evaporated. The residue is purified bydry-column" chromatography on silica gel, using ethyl acetate assolvent. The product is recrystallized to give N-cyclopropanemethyl-2-methoxy-2-( 2-pyridyl)thioacetamide.

Similarly, using in place of cyclopropanemethylamine hydrochloride, thefollowing:

cyclobutanemethylamine hydrochloride cyclopentanemethylaminehydrochloride cyclohexanemethylamine hydrochloride ucts are,respectively:

N-cyclobutanemethyl-2-methoxy-2-( 2- pyridyl)thioacetamideN-cyclopentanemethyl2-methoxy-2-( 2- pyridyl)thioacetamide A iN-cyclohexanemethyl-2-methoxy-2 (2- pyridyl)thioacetamide.

the prod- EXAMPLE 13 By the procedure of Example 10, using in place of2- methoxy-2-(2-pyridyl)thioacetamide, the following:

2-methoxy-2-(2-pyrrolyl)thioacetamide2-methoxy-2-(2-quinolyl)thioacetamide2-methoxy-2-(2-pyrimidyl)thioacetamide2-methoxy-2-(4-thiazolyl)thioacetamide the prod ucts are, respectively:

N-cyclopropyl-2-methoxy-2-(2-pyrrolyl)thioacetamideN-cyclopropyl-2-methoxy-2-(2- quinolyl)thioacetamideN-cyclopropyl-2-methoxy-2-(2- pyrimidyl)thioacetamideN-cyclopropyl-Z-methoxy-2-(4- thiazolyl)thioacetamide.

Similarly, the corresponding N-cyclobutyl, N- cyclopentyl andN-cyclohexyl compounds are prepared.

EXAMPLE 14 By the procedure of Example 12, using the appropriate2-alkoxy-2-heterocyclic-thioacetamide, the following products areprepared:

N-cyclopropanemethyl-2-methoxy-2-(2-pyrrolyl )thioacetamideN-cyclopropanemethyl-2-methoxy-2-(2- quinoly1)thioacetamideN-cyclopropanemethyl-2-methoxy-2-(2- pyrimidyl)thioacetamideN-cyclopropanemethyl-2-methoxy-2-(4- thiazolyl)thioace tamide.

EXAMPLE 15 Z-(Methoxymethyl)pyridine (1.85 g., 0.015 mole) in 15 ml. ofdry benzene is added dropwise to a chilled solution of phenyl lithium(8.1 ml. of 2.1 molar solution, 0.017 mole) in 15 ml. of dry benzene.After the addition is complete, the mixture is stirred at C. for onehour. Phenyl isothiocyanate (2.03 g., 0.015 mole) in m1. of dry benzeneis added dropwise and the mixture is allowed to come to room temperaturegradually, then the mixture is stirred overnight. The mixture is dilutedwith 50 ml. of water and acidified with dilute hydrochloric acid. Thelayers are separated and the organic layer is washed several times withwater. The aqueous layers are combined, basified with dilute aqueoussodium hydroxide solution and extracted several times with chloroform.The chloroform extracts are combined, washed once with brine and driedover magnesium sulfate. The solvent is removed under reduced pressure togive an oil which is placed on a silica gel dry-column, eluting withethyl acetate to give, after cooling and recrystallizing from ethylacetate/hexane, 2-methoxy-N-phenyl-2-(2-pyridyl)-thioacetamide, m.p.97-98.5C.

EXAMPLE 16 By the procedure of Example 6, using the appropriate sodiumalkoxide in place of sodium methoxide, the following products areobtained:

2-ethoxy-2-(2-pyridyl)thioacetamide 2-propoxy-2-(2-pyridyl)thioacetamide 2-butoxy-2-(2-pyridyl)thioacetamide2-allyloxy-2-(2-pyridyl)thioacetamide 2-cyclopropanemethoxy-2-( 2-pyridyl )thioacetamide.

EXAMPLE l7 2-Methoxy-N-methyl-2-(2'pyridyl)thioacetamide (500 mg.) inether is added to ethereal hydrogen chloride. The resulting precipitateis filtered off and recrystallized from ethanol/ether to give2-methoxy-N- methyl-2-(2-pyridyl)thioacetamide hydrochloride.

By the same procedure, the hydrochloride salt of 2-methoxy-2(2pyridyl)thioacetamide is prepared.

EXAMPLE 18 One gram of 2-methoxy-2-(2-pyridyl)thioacetamide in ethanolis treated with an equimolar amount of maleic acid in ethanol to give,after removing the solvent under reduced pressure, 2-methoxy-2-(2-pyridyl)thioacetamide maleate.

1n the same manner, using citric acid, the citrate salt of2-methoxy-2-(2-pyridyl)thioacetamide is prepared.

EXAMPLE 1? To a stirred solution of 11.8 g. (0.1 mole) of 2-pyridylacetonitrile in dry dimethylsulfoxide at 10C. is added 0.1 moleof sodium hydride (dispersed in mineral oil). After 20 minutes, 0.1 moleof chloromethyl methyl ether is added with cooling and the mixture iskept at 10C. for 2 hours. then allowed to warm to room temperatureovernight. The reaction mixture is poured into water and extracted withether. The organic phase is washed with water, dried over anhydroussodium sulfate, concentrated under vacuum and distilled to give3-methoxy-2-(2-pyridyl)propionitrile.

Two grams of 3-methoxy-2-(2-pyridyl)propionitrile is dissolved in 1.5 g.of triethylamine and 2 g. of dry pyridine, saturated with hydrogensulfide. The mixture is heated at C. in a sealed bomb for 15 hours. Themixture is cooled, diluted with water and extracted with ether. Theorganic phase is dried, the solvent is removed and the residue isrecrystallized from benzene/- petroleum ether to give3-methoxy-2-(2-pyridyl)- thiopropanamide.

EXAMPLE 20 By the procedure of Example 19, using in place of 2-pyridylacetonitrile, the following:

2-pyrimidylacetonitrile 4-thiazolylacetonitrile the products are,respectively:

3-methoxy-2-(2-pyrimidyl)thiopropanamide 3 -methoxy-2-(4-thiazolyl)thiopropanamide.

EXAMPLE 21 By the procedure of Example 19, using 2-bromoethyl ethylether in place of chloromethyl methyl ether, the product is4-ethoxy-2-(2-pyridyl)thiobutanamide.

Similarly, using 2-bromoethyl methyl ether, the product is4-methoxy-2-(2-pyridyl)thiobutanamide.

EXAMPLE 22 in the procedure of Example 1, using the following in placeof methyl isothiocyanate:

ethyl isothiocyanate propyl isothiocyanate butyl isothiocyanate theproducts are, respectively:

N-ethyl-2-methoxy-2-(2-pyridyl)thioacetamide 2-methoxy-N-propyl-2-(2-pyridyl)thioacetamide N-butyl-2-methoxy-2-( 2-pyridyl)thioacetamide.

EXAMPLE 23 A mixture of 18.1 g. of methyl 2-methoxy-2-(2-pyridyl)-acetate and 10 g. of dimethylamine in ethanol is stirred atroom temperature for 26 hours. The mixture is concentrated, dissolved inchloroform and extracted with brine. The organic phase is dried overmagnesium sulfate and filtered and the solvent is removed under reducedpressure to give 2-methoxy-N,N- dimethyl-2-(2-pyridyl)acetamide.

Alternatively, 2-methoxy-N,N-dimethyl-2-( 2- pyridyl)-acetamide isprepared by the following procedure. 2-Methoxy-2-(2-pyridyl)acetylchloride hydro-' chloride, 22 g., [prepared by reacting 2-methoxy-2-(2-pyridyl)acetic acid in benzene with thionyl chloride] in 100 ml. ofchloroform is added dropwise and with cooling to 50 g. of dimethylaminein 100 ml. of chloroform. The mixture is stirred for four hours, then 50ml. of aqueous sodium hydroxide is added and the chloroform solution isdried and concentrated to give 2-methoxy-N,N-dimethyl-2-(2-pyridyl)-acetamide.

Phosphorus pentasulfide (4 g.) is added to 9.7 g. of2-methoxy-N,N-dimethyl-2-( 2-pyridyl)acetamide in 25 ml. of pyridine.The mixture is heated on a steam bath for 2 hours, then 250 ml. of waterand ml. of 5% aqueous sodium hydroxide solution are added. The mixtureis extracted with chloroform and the extracts are dried and concentratedand the residue is recrystallized to give 2-methoxy-N,N-dimethyl-2-(2-pyridyl)- thioacetamide.

EXAMPLE 24 Alternatively, 2-methoxy-N ,N-dimethyl-2-( 2-pyridyl)-thioacetamide is prepared by the following procedures.

To 0.10 mole of phenyl lithium in 100 ml. of benzene/ether at 0C. isadded dropwise 10.6 g. (0.084 mole) of 2-(methoxymethyl)pyridinedissolved in 75 ml. of benzene. To this mixture is added dropwise 10.0g. (0.081 mole) of N,N-dimethylthiocarbamoyl chloride in 100 ml. ofbenzene. The resulting mixture is stirred at room temperature overnight,then poured into 100 ml. of water and acidified. The organic phase isextracted once with dilute aqueous acid. The combined aqueous phases areextracted twice with ether, then made basic to about pH 10 and extractedthree times with chloroform. The combined chloroform extracts are driedover magnesium sulfate and the solvent is removed by evaporation. Theresidue is chromatographed, then distilled in vacuo to give 2-methoxy-N,N-dimethyl-2-(2-pyridyl)thioacetamide.

Alternatively, using N,N-dimethylcarbamoyl chloride in the aboveprocedure gives 2-methoxy-N,N- dimethyl-2-(2-pyridyl)-acetamide which isconverted to the thioacetamide by reaction with phosphorus pentasulfideby the procedure described in Example 23.

EXAMPLE Using the following N,N-di-lower alkylthiocarbamoyl chloridecompounds in the procedure of Example 24:

N,N-diethylthiocarbamoyl chloride N,N-dipropylthiocarbamoyl chlorideN,N-dibutylthiocarbamoyl chloride the products are, respectively:

N,N-diethyl-2-methoxy-2-(2-pyridyl)thioacetamide2-methoxy-N,N-dipropyl-2-( 2-pyridyl)thioacetamideN,N-dibutyl-2-methoxy-2-( 2-pyridyl)thioacetamide.

EXAMPLE 26 To a solution of g. of sodium borohydride in 1250 ml. ofmethanol at 0C. is added 350 g. of 2- pyridyl methyl ketone in 300 ml.of methanol with stirring. After stirring for four hours at 0-5C.,glacial acetic acid is cautiously added dropwise, followed by ice andconcentrated hydrochloric acid. The acidic solution is made basic withaqueous sodium hydroxide and extracted with dichloromethane. The organiclayer is dried over magnesium sulfate, concentrated and distilled togive 1-(2-pyridyl)ethanol.

To a stirred solution of 223 g. of 1-(2-pyridyl)- ethanol in 1500 ml. ofdry dimethylsulfoxide is added 2.3 moles of sodium hydride in portions,under nitrogen, maintaining the temperature at 20 C. After two hours,331 g. of methyl iodide is added at 20C. After stirring for anotherthree hours, the mixture is poured onto ice-water and extracted threetimes with ether. The organic phase is washed with water, dried overmagnesium sulfate, concentrated in vacuo, and the residue is distilledto give 2-(l-methoxyethyl)pyridine.

To a solution containing 0.42 moles of phenyl lithium in 400 ml. of dryether under nitrogen, is added 57.5 g. of 2-( l-methoxyethyl)pyridine in50 ml. of dry ether at '-10C. over 20 minutes. After stirring another 15minutes at 10C, a solution of 52 g. of N,N-dimethylthiocarbamoylchloride in ml. of benzene-ether (3:2) is added. The mixture is stirredfor three hours at 10C. and poured into ice-water.

Ice cold 6N hydrochloric acid is added until the mixture is acidic, andthe aqueous phase is separated, washed twice with cold dichloromethaneand made basic with aqueous sodium hydroxide solution. The mixture isextracted with dichloromethane and the organic phase is dried overmagnesium sulfate and the solvent is removed in vacuo. The residue isdecolorized with charcoal in benzene and recrystallized to give 2-methoxy-N ,N-dimethyl-2-( 2-pyridyl )thiopropanamide m.p. 67.870C.

2-Pyridyl ethyl ketone (prepared by adding 2- pyridinecarbonitrile intetrahydrofuran to ethyl magnesium chloride in ether, refluxing for 24hours, pouring onto ice, adding 25% sulfuric acid, then basifying,extracting with ether and drying and concentrating the extracts) is usedin place of 2-pyridyl methyl ketone in the above procedure to give2-methoxy-N,N-dimethyl- 2-( 2-pyridyl)thiobutanamide.

Similarly, using 2-pyridyl butyl ketone (prepared fromZ-pyridinecarbonitrile and butyl magnesium chloride by the aboveprocedure) in place of 2-pyridyl methyl ketone, the product is2-methoxy-N,N- dimethyl-2-(2-pyridyl)thiohexanamide.

In the same manner, using in the above procedure, the followingheterocyclic alkyl ketones:

2-quinolyl methyl ketone 4-pyrimidyl methyl ketone 2-thiazolyl methylketone the products are, respectively:

2-methoxy-N,N-dimethyl-2-(2-quinolyl)thiopropanamide2-methoxy-N,N-dimethyl-2-(4-pyrimidyl)thiopropanamide2-methoxy-N,N-dimethyl-2-(2-thiazolyl)thiopropanamide.

EXAMPLE 27 Ingredient Amount 2-Methoxy-N-methyl-2-( ZyritiyD-Ihioacetamide 100 mg.

hydrochloride Lactose I mg. Magnesium stearate 5 mg.

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 28 Ingredient Amount Z-Methoxy-N,N-dimethyl-2-( 2-pyridyl)- 150mg.

thioacetamide Calcium sulfate dihydrate 125 mg. Sucrose 25 mg. Starchmg. Talc 5 mg. Stearic acid 3 mg.

s tilt...

in which:

m is 0, l or 2; R, is 2-pyridyl;

R is lower alkyl, allyl or cyclopropanemethyl;

s N NH-phenyl or Nl-l-(CH ),.-cycloalkyl, said cycloalkyl having 3-6carbon atoms;

R is hydrogen or lower alkyl;

R and R are hydrogen or lower alkyl and n is 0 or 1 or apharmaceutically acceptable acid addition salt thereof.

2. A compound of claim 1 in which R, is hydrogen.

3. A compound of claim 1 in which m is O.

4. A compound of claim 1 in which m is 0, R is methyl, R is NH-(loweralkyl), N(lower alkyl) or NH- (CH -cycloalkyl and R is hydrogen ormethyl.

5. A compound of claim 1 said compound being 2-methoxy-N-methyl-2'(2-pyridyl)thioacetamide.

6. A compound of claim 1 said compound being 2-methoxy-N,N-dimethyl-2-(Z-pyridyl )thiopropanamide.

7. A process of preparing a compound of claim 1 in which R is NH-(loweralkyl), NH-phenyl or NH (CH ),,-cycloalkyl which comprises reacting analkoxyalkyl-heterocycle of the formula:

R3 is in which m, R R and R are as defined in claim 1, with a strongbase and then with an isothiocyanate of the formula:

R'NCS in which R is lower alkyl, phenyl or (CH ),.-cycloalkyl, saidcycloalkyl having 3-6 carbon atoms and n is O or 1.

8. A process of claim 7 in which R, is hydrogen.

9. A process of claim 7 in which m is 0.

10. A process of claim 7 in which m is 0, R is 2- pyridyl, R is methyl,R is NH-methyl, R is hydrogen and R is methyl.

1. A COMPOUND OF THE FORMULA:
 2. A compound of claim 1 in which R4 ishydrogen.
 3. A compound of claim 1 in which m is
 0. 4. A compound ofclaim 1 in which m is 0, R2 is methyl, R3 is NH-(lower alkyl), N(loweralkyl)2 or NH-(CH2)n -cycloalkyl and R4 is hydrogen or methyl.
 5. Acompound of claim 1 said compound being2-methoxy-N-methyl-2-(2-pyridyl)thioacetamide.
 6. A compound of claim 1said compound being 2-methoxy-N,N-dimethyl-2-(2-pyridyl)thiopropanamide.7. A process of preparing a compound of claim 1 in which R3 is NH-(loweralkyl), NH-phenyl or NH-(CH2)n-cycloalkyl which comprises reacting analkoxyalkyl-heterocycle of the formula:
 8. A process of claim 7 in whichR4 is hydrogen.
 9. A process of claim 7 in which m is
 0. 10. A processof claim 7 in which m is 0, R1 is 2-pyridyl, R2 is methyl, R3 isNH-methyl, R4 is hydrogen and R'' is methyl.